A. KURSAT BOZKURT, MD

University of Istanbul

Cerrahpasa Medical Faculty

2013

Ultrasound assisted

thrombolysis for VTE:

Turkish experience

Pulmonary embolism:

a silent killer

Cause of Death # of annual deaths2

PE Up to 200,0002,3

AIDS 18,017

Breast Cancer 40,870

• Most patients who die from PE are not diagnosed at premortem, and are not even suspected premortem

Study AutopsiesPE

present

PE suspected

premortem

Rubenstein et al4 1.276 44 14 (32%)

Stein and Henry5 404 59 6 (30%)

Lau6 11,044 116 27 (23%)

Pulido et al7 1.032 231 42 (18%)

1. Dalen et al. Prog Cardiovasc Dis. 1975;17:259-70.

2. Wood. Chest 2002;121;877-905.

3. Silverstein et al. Arch intern Med 1998;158:585-93.

4. Rubenstein et al. Arch Intern Med. 1988 Jun;148(6):1425-6.

5. Stein and Henry. Chest 1995 Oct;108(4):978-81

6. Lau. Ann Acad Med Singapore. 1995 May;24(3):356-65.

7. Pulido et al. Chest. 2006 May;129(5):1282-7

Risk stratificationPatient risk stratification (per AHA 2011 guidelines)

Massive PE Submassive PE Minor/Nonmassive PE

High risk Moderate risk Low risk

•Sustained hypotension (systolic BP <90

mmHg for 15 min)

•Inotropic support

•Pulselessness

•Persistent profound bradycardia (HR <40

bpm with signs or symptoms of shock)

•Systemically normotensive

(systolic BP 90 mmHg)

•RV dysfunction

•Myocardial necrosis

•Systemically normotensive

(systolic BP 90 mmHg)

•No RV dysfunction

•No myocardial necrosis

RV dysfunction• RV/LV ratio > 0.9 or RV systolic dysfunction on echo

• RV/LV ratio > 0.9 on CT

• Elevation of BNP (>90 pg/mL)

• Elevation of NTpro-BNP (>500 pg/mL)

• ECG changes

• new complete or incomplete RBBB

• anteroseptal ST elevation or depression

• anteroseptal T-wave inversion

Jaff et al. Circulation 2011;123(16):1788-1830.

Why treat submassive PE

aggressively?RV/LV ratio > 0.9 is an independent predictor of mortality1-4

Patients with persistent RV dysfunction at discharge:

• 8 times more likely to have recurrent PE• 4 times higher mortality rate

than patients with RV dysfunction regressed at discharge5

1-year follow-up, 44% of PE patients with RV dysfunction at hospital discharge will have chronic pulmonary hypertension6

1. Quiroz, Circ 2004; 109:2401-24042. Frémont, Chest 2008; 133;558-362

3. Schoef, Circ 2004; 110:3276-3280

4. Kucher, Arch Intern Med 2005; 165:1777-1781

5. Grifoni, Arch Intern Med 2006; 166:2151-215

6. Ribeiro, Circ 1999;99:1352-1330

ULTIMA Trial

A Prospective, Randomized, Controlled study of

ULTrasound Accelerated ThrombolysIs for the

Treatment of Acute PulMonAry Embolism

- Acute Symptomatic PE confirmed w/ CTA chest

- RV/LV ratio > 1 on echo

1.28

0.99 0.95

0.5

1.0

1.5

Baseline 24 hrs 90 days

RV

/LV

Rat

io

EKOS®+Heparin

1.20 1.17

0.98

Baseline 24 hrs 90 days

Heparin

P<0.0001

P<0.0001

P=0.31

P<0.0001

RV/LV ratio (echo)

Kucher 2013

0.300.38

0.0

0.2

0.4

0.6

Baselineto 24 hrs

Baselineto 90 days

Re

du

ctio

n in

RV

/LV

Rat

io

EKOS®+Heparin

0.030.22

Baselineto 24 hrs

Baselineto 90 days

Heparin

P<0.0001

P=0.03

Primary endpoint: Reduction in RV/LV ratio (echo)

Kucher 2013

Conclusions

In PE pts at intermediate risk of death, low-dose catheter-

directed ultrasound-accelerated thrombolysis (< 20 mg rt-

PA/15 hrs) was superior to anticoagulation with heparin alone

in reversing RV dilatation & dysfunction @ 24 hrs, w/o an

increase in bleeding complications

Although there was a late “catch-up” w/heparin alone, there

was greater improvement

SEATTLE II Study

Submassive and massive pulmonary Embolism

treatment with AcceleraTed ThromboLysis thErapy

STUDY CHAIR: Sam Z. Goldhaber, MD

Women And Brigham’s Hospital, Boston, MA

PURPOSE

Determine if the EKOS EkoSonic® Endovascular Device when

used in conjunction with recombinant t-PA as a treatment for

acute pulmonary embolism (PE) will decrease the ratio of RV

to LV diameter

SEATTLE II Study

STUDY DESIGN

• Single arm, prospective study (20

clinical sites in the U.S.)

• All subjects receive anticoagulation

therapy with 24 mg of Activase

delivered via the EkoSonic® System

• Subjects with acute pulmonary

embolism confirmed by CT

– Massive PE (syncope, systemic

arterial hypotension, cardiogenic

shock, or resuscitated cardiac

arrest)

– Submassive PE (RV diameter-to-

LV diameter ≥ 0.9 on contrast-

enhanced chest CT)

EFFICACY

decrease the ratio of RV to LV diameter within 48 ± 6 hours in

patients with massive or submassive PE

SAFETY

Frequency of major bleeding within 72 hours of initiation of

therapy

SEATTLE II Study

EKOS®

?

0

20

40

60

80

100

120

140

Rapid enrollmentPlanned:

150 patients to

enroll in 18 mo.

Actual:

150 patients

enrolled in 9 mo.

DVT

Deep venous thrombosis (DVT) - 500,000-600,000 new cases in US annually1

- 40-60% of pts on anticoagulation will develop PTS

after 1st episode of DVT2

Post thrombotic syndrome (PTS)- clinical complication of DVT can be lifestyle limiting

and debilitating

- Sx: pain, edema, varicosities, skin discoloration,

thickening & ulceration

- 500,000-600,000 venous ulcers yearly3

- Nearly 90% of patients are unable to work due to leg

symptoms 10 years after iliofemoral DVT4

- Suspect MILLIONS suffer from PTS

Estimated socioeconomic burden of $ 3 billion

annually4References

1. US surgeon general’s office; 2008. 2. Kahn SR, Shrier I, Julian JA, et al. Ann Intern Med 2008;149:698–707. 3. Pacific Vascular

Symposium 6. Kona, Hawaii, 2009. 4. Kahn SR, Ginsberg JS. Arch Intern Med 2004; 164:17–265. Lazarusetal. Arch Dermotolgy

1994; 130:489-93.

Single-center experience

Retrospective, single center case reviews 106 patients and 122 limbs treated

- 66 M, 40 F- Mean age 57; range 13-96 years old- 17 upper and 105 lower extremities - IVC involvement in 25 (24%)

Documented DVT by USAll patients had symptoms > 1mo DVT defined as chronic by age of sx onset > 1moAll with varying degrees of PTS symptoms:

- Pain & swelling ulcer & gangrene ( > CEAP 3, Villalta > 10)- All c/o QOL & lifestyle limitations

Garcia et al. SIR 2012 Presentation & Press Release

Methods

Case review data was collected including:

- DVT history

- Procedural information

- Immediate technical outcomes

- Symptomatic improvement

- Ultrasound follow-up at 1,3,6, and 12 months, and yearly thereafter

Minimally Invasive endovascular techniques included:

- Initial PTA- ultrasound accelerated thrombolysis (EKOS)- PCBs- Adjunctive therapies (stenting, PMT)- Anticoagulation- ECS

Results

Symptomatic Improvement

Mean follow-up: 2 yrs 7 mo

104 of 122 limbs:- 97 (93%) reported

significant

improvement

- 7 (7%) unchanged

- 0 worse

- 18 were lost to follow-up

0

20

40

60

80

100 93

70

Significant Improvement

Unchanged

Worse

Results

US Patency ( % Remaining open)

1 mo: 95 of 100 (95%)

3 mos: 71of 77 (92%)

6 mos: 57 of 65 (88%)

12 mos: 30 of 38 (79%)

24 mos: 11 of 19 (58%)

95 92 8879

58

0102030405060708090

100

1 3 6 12 24

Patent Limbs (%)

The Key is Removing the Clot

There are two challenges

1. Transport the drug TO the clot (Delivery Catheter)

2. Further transport the drug INTO the Clot(Ultrasound Core)

Time 0

Wait 30 Minutes…

+ Lytic Lytic

+ Ultrasound

In Vitro Thrombus Model(Human Platelet-Poor Plasma Clots)

Control

9.15

5.84.2

1

3

5

7

9

C L+ LUS+

Time 30

Min.

In Vitro Thrombus Model(Human Platelet-Poor Plasma Clots)

Clot

Weight

(grams)

Ultrasound enhances lytic agents

equally

0

20

40

60

80

100

UK rtPA reteplase

25 0.002 0.0009

Drug Type and Conc. in [mg/ml plasma]

Lysis

En

ha

nce

me

nt F

acto

r

[%]

1. Clot is made up of tight fibrin strands.• The strands protect the clot

2. Plasminogen is present in the clot• When Activated: Plasminogen converts to Plasmin

• Plasmin eats fibrin

3. tPA activates plasminogen• Creating more plasmin to digest fibrin

4. The speed of lysis depends on ability of lytic to access plasminogen receptors sites.*

What we know about the Clot?

* Francis, Charles W. et al. “Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator into Clots.”

Ultrasound in Medicine and Biology 21.3 (1995):419-424.

WITH ULTRASOUND

ENERGY

WITHOUT ULTRASOUND

ENERGY

How Ultrasonic Energy Unlocks The Clot…

Mechanism of Action Ultrasonic energy causes fibrin

strands to thin, exposing plasminogen receptor sites and fibrin strands to loosen

Thrombus permeability and lytic penetration are dramatically increased

Ultrasound pressure waves force lytic agent deep into the clot and keep it there

Thrombolysis results

…With No Evidence of Fibrin Strand Breakage4

ULTRASOUND ENERGY

& THROMBOLYTIC

Ultrasound Accelerated Thrombolysis

4Braaten, J., Goss, R., and Francis, CW. “Ultrasound Reversibly Disaggregates Fibrin Fibers.”

Thromb Haemost 78 (1997) 1063-8.

µSonic pressure waves

Mechanism of Action

- Ultrasound pressure waves pass through the thrombus all the way to the

vessel walls and behind venous valves.5

- The microsonic energy causes the fibrin strands to thin, exposing

plasminogen receptor sites. That makes the thrombus more permeable

and allows the lytic to penetrate deeper.6

5Parikh, S., Motarjeme, A., et. al. “Ultrasound-Accelerated Thrombolysis for the Treatment of Deep Vein Thrombosis: Initial Clinical Experience”. Journal of Vascular and Interventional Radiology, Volume 19, Issue 4, April 2008, pp 521-528.

6Francis, CW. et al. “Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator into Clots”. Ultrasound in Medicine and Biology 21.3 (1995): 419-424.

Microsonic pressure waves

Ultrasound Accelerated Thrombolysis

6cm

Treatment

Zone

Microsonic …mechanism of action

Standard Infusion Catheter

Spread of

Stained t-PA

Plasma ClotPlasma Clot

Spread of Stained t-PA

EkoSonic Endovascular

Device

Thrombus exposed to ultrasound absorbed 48% more t-PA in one hour, 84% more t-PA in two hours and 89% more t-PA in 4 hours than thrombus not exposed to microsonic pressure.7

Ultrasound Accelerated Thrombolysis

7Francis, CW, et al. “Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator into Clots.” Ultrasound in Medicine and Biology 21.3 (1995): 419-424.

>99% of Ultrasound Energy passes through the valves

Bringing Ultrasound to

Thrombolysis

Even behind the valves

Turkish Experience

August 2010 – October 2013

284 PE

761 DVT

No reliable follow-up

11.7% stenting

Reported major complications

- 1 dead during PE treatment

- 2 major bleeding

THANKS